Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats
Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats
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DOI：
10.1002/bdd.2242
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发表时间：
2020-06-25
影响因子：
2.1
通讯作者：
Okuda, Masahiro
中科院分区：
文献类型：
--
作者：
Hiramatsu, Shun-ichi;Ikemura, Kenji;Okuda, Masahiro
顺铂被广泛用于治疗多发性实体瘤。顺铂引起的肾毒性是顺铂通过人有机阳离子转运蛋白2(HOCT2)在肾内蓄积所致。由于已知质子泵抑制剂兰索拉唑可以抑制hOCT2的活性，兰索拉唑可能会减轻顺铂引起的肾毒性。先前的一项研究表明，同时给予兰索拉唑可以改善接受顺铂治疗的患者的肾毒性。然而，具体的机制仍有待澄清。在本研究中，利用hOCT2表达的培养细胞和大鼠肾切片研究了兰索拉唑和顺铂之间的药物相互作用。此外，还研究了兰索拉唑对顺铂肾毒性的影响及顺铂在大鼠体内的药代动力学。在摄取研究中，兰索拉唑有效地抑制了表达hOCT2的培养细胞和大鼠肾切片对顺铂的摄取。体内研究表明，兰索拉唑可显著减轻顺铂所致的肾毒性，在顺铂腹腔注射后72小时，其肾内铂的蓄积量约为顺铂的60%。此外，静脉注射顺铂和兰索拉唑的大鼠在静脉注射顺铂3min后，肾脏对铂的摄取减少到单独使用顺铂的78%。此外，静脉注射顺铂后3min，兰索拉唑治疗组和未治疗组大鼠的血浆铂浓度无显著差异。这些结果表明，兰索拉唑通过抑制rOCT2介导的顺铂在大鼠体内的摄取，从而减少顺铂在肾脏中的蓄积，从而减轻了顺铂所致的肾毒性。目前的发现为建立新的保护方法以最大限度地减少顺铂引起的肾毒性提供了重要信息。
Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. Thein vivorat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.